Modulation of the inositol 1,4,5-trisphosphate receptor (IP(3)R) by the immunophilin FK506 binding protein (FKBP)

摘要

The inositol 1,4,5 trisphosphate receptor (IP$sb3$R) is a tetrameric calcium release channel expressed in a diversity of cell types (for review see Furuichi, 1995). In response to the intracellular second messenger inositol trisphosphate (IP$sb3)$ the IP$sb3$R mediates release of calcium from intracellular stores (for review see Irvine, 1992). Rises in intracellular calcium levels are responsible for the activation of numerous enzymes critical to cellular operations, such as Ca$sp{2+}$ dependent kinases, Ca$sp{2+}$ dependent phosphatases, and Ca$sp{2+}$ sensitive regulators of gene transcription (for review see Clapham, 1995). The cell controls intracellular Ca$sp{2+}$ levels very tightly in a temporal and spatial fashion largely through modulation of the IP$sb3$R and the ryanodine receptor (RyR), a related tetrameric Ca$sp{2+}$-release channel (for review see Sorrentino, 1993). Study of the modulation of IP$sb3$R is therefore informative as to basic aspects of cell biology and specifically signal transduction in neurons as well as other cell types.;Recent work has demonstrated an interaction of RyR with the immunophilin FK506 binding protein (FKBP) (Jayaraman, 1992). This small ubiquitous protein has been shown to exist in a physical complex with RyR and modulate the Ca$sp{2+}$ flux characteristics of that channel by a mechanism which has not yet been fully elucidated (Timerman, 1993, Brillantes, 1994). It has been postulated that FKBP may be an important protein in signal transduction pathways following its identification as the target of the immunosuppressant drug FK506. FK506 disrupts a Ca$sp{2+}$ dependent signal transduction cascade in T cells (for review see Schreiber, 1992). The cellular role of FKBP in the absence of the drug remains unclear. The work outlined in this thesis attempts to investigate aspects of signal transduction in the brain by examining the possibility of modulation of IP$sb3$R by FKBP.